Dr Davis links

I browse Dr Davis' blog occasionally. Although Dr D seems to be a total cholesterol believer and has his sights set on 60:60:60 for HDL, LDL and Trigs (and goes with the drug therapy needed to get there) he does have very extensive experience of getting people to change their eating habits. His dislike of wheat seems to come more from using it as a metaphor for junk food, but the addiction aspect is clearly up there too. This post and this one drop in to that last category.

I really like this one too. Been reading Sholokhov's "Virgin Soil Upturned". I'm thankful to be able to make food choices. I'm never hungry. I am grateful.

And then we have this one too. The beginnings of saturated fat acceptance!!!! Woo hoo. Here's the bit I like:

"Adding back saturated fat. I say "adding back" since most of us (including myself) went too far down the "saturated fat is bad" path over the past few years. While I do not advocate a carte blanche approach to saturated fat, I believe that adding back eggs (preferably free-range and/or omega-3 rich), lean meats, and hard cheeses is a good idea"

Okay, it's cautious, but its a shift in the right direction. Bring on the carte blanche and let the chickens choose their own weeds. Of course there's not a lot of saturated fat in eggs, so here we have cholesterol acceptance too, if only dietary... That's nice to read.

Peter

Metabolism nuts and bolts PUFA

This post is basic biochemistry that we probably all know. I've just stuck it down as I've slogged through it while I've been working through Chris Masterjohn's treatise on PUFA, it seems a waste not to use it. Ignore if you're happy with elongase and desaturase enzymes.

Omega counted double bonds are very straight forward, they are counted from the methyl end of a long chain fatty acid. Because mammals can't add extra chain length or desaturate at the methyl end, these bonds are "fixed" in their identity. So mammals can pop a double bond in to stearic acid in the omega 9 position to give oleic acid and that's it as far as the methyl end is concerned. Double bonds at the omega 3 and 6 positions are also fixed and come from the diet (mostly, there may be an exception). No chance of elongating at the methyl end, so the 9th/6th/3rd will always be the ninth (or 6th or 3rd) bond down from the omega end of the chain. So oleic acid is an omega 9 fat and all of its derivatives are too. Whatever elongation/desaturation happens, it happens at the carboxyl end. Ditto omega 3s and 6s.

Delta refers to desaturase enzyme's ability to change a single bond to a double bond, extracting two hydrogen atoms in the process. So delta 6 desaturase pops a double bond in to the place of the 6th carbon-carbon bond, counting from the carboxyl group end of a fatty acid. This number is the alpha number, as it's counted from the opposite end to omega number. The desaturases mostly don't care how long the fatty acid is, they just grab the acid end, count six (or seven or nine or five etc) and stick in a double bond.

We definitely have a delta 5 and a delta 6 desaturase. Oddly enough we never put double bonds in to adjacent locations in our fatty acid carbon chains, there is always a gap. The pattern goes double bond, two singles, double, two singles etc, as far as I can see. That is if you want extra double bonds at all.

Fatty acids get elongated. This always happens from the carboxyl end, and always involves adding two extra carbon atoms, using single bonds only. In mammals anyway.

So when the fatty acid with a recently added double bond placed in the alpha 6 position by our delta 6 desaturase gets elongated, that new double bond gets promoted from the alpha 6 position to the alpha 8 position.

To keep the pattern we want two single C-C bonds then the new double. That mean going for the 5th C-C bond using delta 5 desaturase.

This neatly gives us the end product of arachidonic acid from linoleic acid.

We also get to eicosapentaenoic acid (EPA) by the same pathway if we start from the alpha linolenic acid parent. Then a simple elongation and a delta 4 desaturation gives docosahexanoic acid (DHA). If your delta 4 desaturase doesn't work you can try this:

Double elongation w/o desaturation to 24 C chain with first double bond now pushed to the 9 position from the carboxyl end. Delta 6 desaturase places an appropriate double bond at the 6 position, as it always does. This weird fatty acid is then shortened by two c atoms (off of the COOH end of course) to give DHA, the new double bond thus ending up, as it should for DHA, at the 4 position (from the 6 position where it was placed by delta six desaturase).

That last paragraph is from Mary Enig's book "Know Your Fats". The rest is general biochemistry.

There is no arguing with the essentiality of arachidonic acid and probably the same goes for DHA. If we don't get them pre formed in our diet, this is how we make them.

Peter

Gluten links from Bloggeier

My thanks to Bloggeier for these links, especially for the full text of the letter to GUT from the Spanish group.

These are various groups who are interested in innate gluten toxicity (GUT letter), non antibody investigation of food sensitivity and combined reactivity to gluten and casein in some coeliacs.

Quotes from the letter to GUT, which has restricted access:

"Nowadays it is assumed that an innate immunity to gluten plays a key role in the development of coeliac disease (CD). This innate response, mediated by interleukin (IL) 15 and elicited by "toxic peptides", like the 19-mer, through a DQ2-independent mechanism, induces epithelial stress and reprogrammes intraepithelial lymphocytes into natural killer (NK)-like cells leading to enterocyte apoptosis and an increase in epithelium permeability"

Try telling that to a Nottingham gastroenterologist!

"We consider that, to our knowledge, this is the first time that an IL15-mediated innate response to gliadin and gliadin peptides is described in individuals without CD, as well as an IL15-mediated innate response to the "non-toxic" deaminated immunodominant 33-mer peptide"

The 33 amino acid section is supposed to be non toxic itself (which turns out to be incorrect, it is toxic) but provides a focus for antibody production, which leads to severe secondary damage by the antibody. This still happens.

"Moreover, the IL15-mediated response in patients without CD was also triggered by the toxic 19-mer gliadin peptide (three of six) and, especially, by the 33-mer gliadin peptide (five of six). Importantly, none of the basal cultures produced this cytokine and, although not expected, the "non-toxic" immunodominant 33-mer was also able to induce an innate response"

Of their biopsy samples from NON COELIAC DISEASE people, one out of six did NOT respond to the 33-mer with interleukin 15. Five out of six did. I fully accept that there may be things going on with our immune systems to increase the frequency of allergies (grass pollen has always been around, hay fever was first reported just over 100 years ago as a case report in the Lancet...) but gliadin is directly toxic. It looks like allergy comes later, facilitated by toxicity causing intestinal leakage.

So it is just possible that maybe 1 person in six might NOT respond adversely to gluten. Notice that the researchers put "non toxic" in quotation marks, at least twice. These people know what they're talking about. I wonder if any of the group eat digestive biscuits with their coffee at lab meetings?



I'm not sure if I got the full text of the multimodal imaging paper through my athens account or if it's free access, but the interest this group has in getting away from crude antibody tests for food intolerance is impressive. Using some of their techniques would allow you to look at things like salicylate and amine toxicity, which probably have nothing to do with antibody production and very little to do with the immune system at all. The sort of sensitivity that gets you labeled as a malingerer in Nottingham...

Peter

Congratulations: You have coeliac disease!

It may come as a surprise to find that not all people with coeliac disease sit on the loo for all of their lives until the time they get a diagnosis. In fact they perceive themselves as healthy, if it's occult enough.

I posted on what I though of the neurology department at the Queen's Medical Centre in Nottingham when it comes to gluten ataxia: 

Go to Sheffield!!!!!

Now I've stumbled across this glowing account of the benefits of occult coeliac disease, again from the Queen's Medical Centre, Nottingham. Here are a few snippets from the main text:

"EMA positive participants (n=87) were on average slightly lighter by 2.2 kg (p=0.08), were more likely to have reported their general health as being good or excellent"

"EMA positivity was associated with an 8% reduction in mean serum cholesterol (0.5 mmol/l; p less than 0.01) and reductions in mean haemoglobin (0.3 g/dl; p less than 0.01)"

"Those affected report "better health" but they do have an increased risk of osteoporosis and mild anaemia. In contrast, they have a favourable cardiovascular risk profile that may afford protection from ischaemic heart disease and stroke"

"The important finding of a favourable cardiovascular risk profile in these individuals suggests that any screening programme of the general population would need to be carefully evaluated in terms of risks and benefits before its introduction"

That last snippet needs to be read very carefully.

To summarise: In Nottingham, undiagnosed coeliac disease is good for you. Never mind the occasional fracture, bowel cancer or auto immune neuropathy. And I'm trying not to grind my teeth at the stupid glee over lower than average total cholesterol (in a predominantly female population!). It's obviously better to die of bowel cancer than a heart attack. Well, if you're a Nottingham epidemiologist that seems to be the case.

Let's just head over to Northern Ireland for a while (rather than Sheffield, we want a more general overview this time). The first point is that the anti-endomysial antibody test is pretty rubbish. To quote McMillan et al:

"EmA-negative coeliac disease is common. Reliance on EmA testing to select patients for biopsy will result in significant underdiagnosis"

So obviously the benefits of coeliac disease, so popular at the Queen's Medical Centre, are more widespread than we realise! Certainly in Northern Ireland. Unfortunately there are certain benefits of occult coeliac disease which Nottingham forgot to mention, particularly death! Again from Belfast:

"Patients with coeliac disease or gluten sensitivity had higher mortality rates than the Northern Ireland population. This association persists more than one year after diagnosis in patients testing positive for anti-gliadin antibodies"

What is meant by "gluten sensitivity"?

"There were 1133 patients who tested positive for anti-gliadin antibodies and they were defined as gluten sensitive"

This later group would not even be considered by Nottingham as being unwell because they don't usually have gut pathology and their anti-gliadin antibodies come and go. How common is this category of sensitivity? McMillan again:

"The results establish that IgA antigliadin antibody prevalence is high at 5.7%"

That's one in eighteen people.

Using an antibody test. Antibody positive patients will only be the very big tip of a massive iceberg. One you start looking at how the innate immune system functions, with its NK cells that don't use antibodies, when challenged by gluten, you have to wonder whether anyone is immune to gluten damage.

You can guess what I think.

BTW If anyone got down to the comments of the gluten ataxia post and read those by Toxic, you can get an idea of how clued up Nottinghamshire seems to be when presented with a person suffering full blown, antibody positive, severe, multisystem gluten damage. They missed it. Lots of times. Not sure if Toxic attended the Queen's Medical Centre, but I'd guess so.

Peter

Physiological insulin resistance; Dawn Phenomenon

What is the Dawn Phenomenon (DP)? A nice simple definition is available from here:

"The dawn phenomenon is a term used to describe hyperglycemia or an increase in the amount of insulin needed to maintain normoglycemia, occurring in the absence of antecedent hypoglycemia or waning insulin levels, during the early morning hours. To be clinically relevant, the magnitude of the dawn increase in blood glucose level should be more than 10 mg/dL or the increase in insulin requirement should be at least 20% from the overnight nadir. Controversy exists regarding the frequency, reproducibility, and pathogenesis of the dawn phenomenon. Approximately 54% of patients with type 1 diabetes and 55% of patients with type 2 diabetes experience the dawn phenomenon when the foregoing quantitative definition is used"

OK, I lied about the simplicity.

If you go back to 1988 this group seemed to think that the Dawn Phenomenon was pretty straight forward and amenable to pharmacological management. In the early hours of the morning humans have a growth hormone (GH) surge. GH causes lipolysis, lipolysis releases free fatty acids. No muscle wants glucose when it has access to free fatty acids. Muscle thus becomes insulin resistant and blood glucose rises. They studied type one diabetics as doing this eliminates all of those messy insulin responses to glucose that normal people produce.

Give an anticholinergic, block the GH surge and you block the DP. All nice and simple.

Then this group, in 1992, went out to check if this was true and gave a bolus of GH, again to some type one diabetics. Any old time of day as far as I can tell.

As expected GH caused a rise in FFAs but no insulin resistance in this paper! Quite how they managed this is a bit beyond me. FFAs should produce insulin resistance. Both papers report comparable peaks in GH but neither gives an AUC for GH. It's difficult to compare FFA changes between papers.

Then, when you get down to the nitty gritty, you find that the second paper was quite careful to produce only a SHORT physiological burst of GH, shorter than occurs at night in humans. They were ONLY looking for the effect of GH on insulin resistance, so they had to keep FFA changes to a minimum. This looks to be a very carefully crafted sentence to me, it's the "summing up" in the abstract (the section of the paper which actually gets read):

"Since no significant effect on glucose metabolism was recorded, we do not presently find evidence to support a primary role for small surges of GH in the pathogenesis of the dawn phenomenon"

A translation might read:

"A bolus of GH which is significantly lower than that needed to produce the lipolysis necessary for the Dawn Phenomenon does not produce the Dawn Phenomenon"

People don't work like this! The nightly GH surge in humans does crank up FFAs. Eliminating this effect from your study won't help elucidate what's happening in the DP, except to say it's not GH per se, but it's still the down stream effects of GH that matter. The 1988 paper looks far more convincing to me.

Current thinking seems to have forgotten about FFAs but does come up with the concept that there is no drop in insulin levels involved. This is interesting in so far as Dr Bernstein suggests that rapid hepatic breakdown of insulin is the cause of the problem. I've yet to see any evidence of this mechanism, unusual for a Dr B idea.

The other main support for FFA involvement is the roll of eating in terminating the DP. This has been discussed many times on the Bernstein forum. Many type two diabetics develop a vicious DP on LC eating and, if they continue to fast through the morning, their blood glucose will just keep going up and up. Eating CARBS stops this, presumably the carbs get insulin high enough to get ahead of the effects of FFAs on muscle, while the extra insulin can shut down hormone sensitive lipase and so drop FFA production... This is physiological insulin resistance taken to pathological extremes.

It's interesting to speculate whether it is the facility to indulge in lipolysis to excess, possibly related to the absolute fat mass available or insulin resistance in those adipocytes, or failure of the cross talk between alpha and beta cells in the pancreas or failure of hepatic vagal nerve supply which makes the DP such a big problem in some diabetics but not in others. I don't know.

Also the how and why of bed time alcohol blocking the DP effect is another big unknown, but it seems to work for many diabetics. Whether this is an hepatic effect, a GH effect or a lipolysis effect seems wide open. Wine lovers with DP just seem grateful when it works for them. Evening alcohol incidentally also drops my morning glucose in to the 4 point something range.

So it looks to me as if the DP is an insulin resistance phenomenon by which GH induced lipolysis bumps up morning glucose. I think this is physiological. When lipolysis is one step ahead of the extra insulin production needed to keep blood glucose in an "acceptable" range you can easily end up with an elevation of FFAs, insulin and glucose all at the same time. In fact, broken insulin sensitivity might well do this, and so you end up with type two diabetes markedly worsened by a GH surge, every night...

Peter

When is a high fat diet not a high fat diet? Stuff via Fanatic Cook

Here's an interesting paper brought my way by Dave Lull who browses Fanatic Cook, a place I'm not likely to visit in my travels. Though perhaps I should, to keep an eye on what the carbophiliac people are up to...

This paper is another in which a Western/Cafeteria diet (45% fat, 40% carbs) is described as high in fat and, wait for it, low in carbohydrate. Assuming 2400kcal per day, that's 1000kcal of carbs or 250g/d. You can appreciate the level of intellectual honesty here, so of course the temptation is to bin the paper. No, WAIT.

There's some interesting stuff. Never mind the shifts in cholesterol levels (it was a cross over study with a low-fat high-carb period), these are exactly what you would expect. The study was careful not to check the LDL particle sizes and numbers otherwise they might have found the small dense LDL which would probably have predominated on the HC period. That is along side the lower HDL figure they did report on the HC phase. They were also careful not to look at glycosylation levels (HbA1c would be useless in a short study like this, but fructosamine looks at two weeks of glycosylation and would have been interesting) to see what was happening in the "eating" world, rather than during a glucose tolerance test. You don't put this sort of control in to nutrition studies because it might not get you the answers you want. High fat diets DO tend to produce higher fasting glucose levels and can even produce higher fasting insulin levels, as here, but 24h AUC for insulin and glucose would be lower. Fructosamine would have shown this. That's how come I can sit here with an HbA1c of 4.4% and a fasting glucose of 5.5mmol/l, higher some days. No suggestion anywhere that Vidon et al or Fanatic Cook see things this way. I do. Shrug.

So, not my type of study. But look at this, this is what grabbed me:

"Lower cholesterol concentrations occurred despite a higher cholesterol synthesis rate (P less than 0.05) and higher HMG-CoA reductase mRNA concentrations (P less than 0.05). LDL receptor mRNA concentrations were unchanged, LRP mRNA concentrations were lower (P less than 0.01)"

The molecular techniques are a bit beyond me to comment on, so I'm just going to believe Vidon et al, that cholesterol synthesis went UP on the high carbohydrate phase diet, plasma levels went DOWN and gene expression for the LRP went DOWN.

Now, they were looking at HMG-CoA reductase in white blood cells, not the liver, but they seem to think the same thing happens in both places:

"Because synthesis and secretion in the plasma pool increased, it appears that the lower plasma cholesterol concentrations were related to increased removal from plasma. However, the mRNA concentrations of 2 main lipoprotein receptors that control the clearance of cholesterol from plasma were unchanged (LDL receptors) or decreased (LRP)"

Now I find this very interesting. More cholesterol produced, less is taken up, yet plasma level drops.

Here's an ad hoc hypothesis as good as anything in the paper:


Some receptor other than the LDLr or the LRP is taking up the LDL cholesterol.


Lets have a guess at which one, let's guess at the oxidised cholesterol receptor. There is at least one short term intervention study showing that small reductions in total fat calories in the diet increase the level of oxidised LDL in the blood, markedly. There was a 15% difference in the fat content of the two diets in Vidon's study. Oxidised LDL is eaten by macrophages, using the oxLDL receptor. They become foam cells in fatty streaks.

Perhaps the cholesterol levels drop as it's all now in foam cells on the arterial walls????

Never forget the American paradox. According the Vidon et al there must a sharp reversal of those benefits associated with increasing fat from 18% of calories through to 32% (p less than 0.001 for trend by quartiles) if you extend it to 45%. Duh.

Maybe, maybe not.

Peter

Ketosis links

There are a couple of posts on ketosis and brain function on Emma's blog that warrant a read, especially with Failsafe additions (read Emma, I don't know much about Failsafe). Ketogenic diets are in the news in the UK for epilepsy management at the moment. With the list of neurotransmitter effects that Emma details there is very clear cut logic to looking down this route for a fairly wide range of brain problems. As well as epilepsy and bipolar disorder I've heard anecdote on Dr Bernstein's forum for Tourette's. Obviously there is a certain amount of stuff about gluten/casein (A1 I presume) and schizophrenia.

Peter

Weight loss when it's hard 5. Son of diazoxide

Life can be mean to you, just on a random chance basis. Sometimes bad stuff just happens.

Imagine what it's like to be planning a study, let's say on the use of a drug for managing atopic dermatitis in dogs, and you've struggled to recruit 20 participants. After the randomisation process you notice that you've ended up having recruited eight West Highland White Terriers (all with pink toes, sweaty armpits and sore ears, many Westies live with atopy) in to the treatment group (n=9) and a heterogeneous mix of healthy mongrels in to the placebo group (n=11). Oh dear. This is a real problem and can happen with small group-size studies. At this point you should consult a statistician or perhaps your group leader, before staking your career on the outcome of this particular study. Suicide is not usually needed, even if considered.

So poor old Due, the first author of a paper produced by Astrup's group in Denmark, struggled through 280 potential participants for his (or her? Dunno) diazoxide study before eventually finding 47 people who conformed to the entry criteria. Twelve of these said get lost. So 35 people started the study. Randomisation and drop outs gave n=13 in the diazoxide group and n=18 in placebo group by the end of the study.

Due got bitten by his patient groups and doesn't appear to even realise it happened! Whoever did the statistics on the participant characteristics of this study noted that the diazoxide group had an average fasting insulin level of 157 pmol/l where as the placebo group had a level of 119 pmol/l, with p less than 0.001 for the difference. Yes, I counted and recounted the number of zero's in this p value. It's not a typo. Oh dear! This never made it in to the discussion, it never even made it in to the results section, just in to a table, so I assume Due never noticed! ! ! ! It must have gotten past two scruntineers too.

Within one week of starting the drug there was a significantly greater drop in the average insulin level of the diazoxide group. Of course there was, this is what the drug does. Even Due noticed this. Because of the way the results table is laid out we only get the differences, down by 50 pmol/l in the diazoxide group, by 5 pmol/l in the placebo group. Again p less than 0.001 when comparing the changes. What Due didn't do was compare the insulin levels at this point BETWEEN groups. The diazoxide group is going to be in the region of 107 pmol/l and the placebo group at this point would be around 114 pmol/l.

I defy anyone to find a statistically or biologically significant difference between the fasting insulin levels at this point.

By the end of the study the fasting insulin values were about 100 pmol/l on diazoxide plus semi starvation versus about 80 pmol/l on semi starvation alone in the placebo group. I've no idea what the p value for the differences between groups might be at this point and Due certainly isn't going to tell us.

Going to table 2 we find that the diazoxide group, which ran a fasting insulin level of just over 100 pmol/l throughout the study lost 4.9kg and the placebo group, which ran a fasting insulin which started at 115 pmol/l and which probably dropped continuously to 80 pmol/l and so probably averaged just below 100 pmol/l, lost 6.4kg.


An aside:

At this point it is certainly worth noting from table 2 in Alemzadeh's paper that the initial fasting insulin levels were the opposite way round to those in Due's paper, tending to emphasise the diazoxide effect (204 pmol/l in the placebo group vs 168 pmol/l in the diazoxide group). Checking the bottom left hand graph of figure 2 shows that this difference was not statistically significant. We have to decide for ourselves if it was biologically significant.



Back to Due's paper:

Averaged over the bulk of the study the placebo group probably had slightly lower insulin levels that the diazoxide group and lost slightly more weight. All non significant, but with no significant difference between insulin levels, why should you expect any significant difference in weight loss?

Diazoxide is not a slimming drug. It reduces insulin levels, which is what allows the weight loss. Whether you drop insulin levels by starvation, diazoxide and starvation, LC eating or becoming muscle bound, insulin is what matters. No differences in insulin, no differences in weight loss.

Of course, it is possible that Due and Astrup were fully aware of what they achieved and thought long and hard about how they presented their results. I don't think so. I sincerely hope not. Stupidity is much more pleasant to consider than deviousness.

Peter



PS I'm not going to discuss the discussion. Due doesn't really discuss anything there anyway, just re states his results, recapitulates those of the original diazoxide paper without understanding where or how the differences in outcome arise and then states that diazoxide is useless for weight loss. There is no synthesis or understanding of what is going on. Probably due to working under Astrup.

PPS It's worth noting that semi starvation DOES drop insulin levels and does increase insulin sensitivity (Matsudas index from 5.91 up to 8.31 in this study) and so does lowering insulin with diazoxide plus semi starvation (Matsudas index up from 5.18 to 9.27). I wonder what 8 weeks of hypocaloric LC eating would do, or even weight stable LC eating...

Weight loss when it's hard 4. Coming soon; son of diazoxide

Particular thanks to both Mark and Stephan for copies of the diazoxide paper by Astrup's group. Looking forward to posting on this one but not sure how time will pan out in the next couple of days! But just goes to show, you REALLY do need the full text, otherwise you get the impression that the two studies conflict each other, and that Astrup is, well, I'd better not put down my opinion of Astrup!

Look here:

The Danish diazoxide group: Can't write a discussion or understand their own results-

Due A, Flint A, Eriksen G, Møller B, Raben A, Hansen JB, Astrup A.

Location: Research Department of Human Nutrition, Royal Veterinary and Agricultural University, Frederiksberg, Denmark


Compare that group to the Danish flavanoid wash out group-who fought tooth and nail to publish a controversial result:

Young JF, Dragstedt LO, Haraldsdóttir J, Daneshvar B, Kall MA, Loft S, Nilsson L, Nielsen SE, Mayer B, Skibsted LH, Huynh-Ba T, Hermetter A, Sandström B.

Location: Department of Human Nutrition, The Royal Veterinary and Agricultural University, DK-1958 Frederiksberg C, Denmark.


Anyone spot any overlap at all between the group members? Two sorts of researchers perhaps, one with a better eye to future funding. Oh, did I say that?

Peter

Weight loss when it's not hard 3. Oops

You just have to be careful. You know what it's like, you're up at 6am with your son, get a quick creamy cocoa as you spoon his breakfast in to him, then it's play play play, then he goes to nursery and you've got to tear down the higgledy piggledy fence, get a decent gate, buy the timber, get it all cut, fitted, creamy cocoa, realise the carport post is so far off of vertical you have some more post fitting to do, run out of time, get your son from nursery, sort out the blog while he naps, play play play, have a hyperlipid supper, sort out the blog while your wife goes to Pilates, do the same thing the next day pretty well identically, but get the verticals vertical, back pack your son to playground play play play, especially the slide, another high fat supper, do some gardening somewhere along the line, sort the blog.

Suddenly you realise you've skipped some calories by accident.

Calories in, calories out. You don't weigh 65kg. That was 48 hours ago. Now 63.8kg is more where it's at despite the gluten free almond based chocolate sponge cake (mmmm, bad carbs in the icing) we had after supper last night. Bodyfat's still at 11% but that's at 9am, it'll be down by this afternoon as it always drops through the day. Except today I'll eat.

YOU HAVE TO REMEMBER TO EAT!

Peter

Weight loss when it's hard 2. Diazoxide

I just thought I'd put this post up as it's fairly topical at the moment.

We all now know that macronutrient ratio is irrelevant, insulin is irrelevant and all that counts is calories. Calories in, calories out, fat people are lazy gluttons. So let's play.

You can simply reduce insulin secretion using diazoxide. Find enough obese people willing to put up with the hunger generating regime supplied by Slimfast and semi starve them for 8 weeks. Half can have a placebo, half get diazoxide in addition to Slimfast starvation. Figure 1 in the results is where you want to look. The idle porkers starving on Slimfast plus diazoxide lost significantly more weight in 8 weeks than the idle porkers starving on Slimfast alone.

It looks to me as if the diazoxide group had lost 10% of bodyweight and were still loosing. The Slimfast alone group were stalled at about 4.5% bodyweight loss. Note also that the diazoxide group lost 9.3kg of fat vs. 3.6kg in the placebo group.

That is, diazoxide produced an excess fat loss of about 5.8kg in eight weeks. That's 100g per day. Or about 900kcal of fat. Every day.

So what's going on. It's pretty obvious really. This is not a metabolic ward study and the subjects cheated. Must have done. Stands to reason. These are free living people. How can any bloke on a 1570kcal per day diet walk past the gym without slipping in and spending an hour doing bench presses? OK, he promised to keep his exercise unchanged but really, no one will ever own up to having a 900kcal/d gym habit like that.

Or maybe the placebo group cheated. It's pretty obvious that 1570kcal of Slimfast will have you pogged out all day, no room for even a teensie weensie little donut, but hell, if they're half price you might force one down or maybe that will be 10 donuts......

But it's funny that the gym sneaks and the donut moonlighters ended up in separate treatment groups.

Or maybe, just maybe, you could just accept that in the real world, outside a meatball ward, sorry, metabolic ward, the level of insulin in your blood stream influences your rate of weight loss, specifically your rate of fat loss.

BTW The folks in this study are clearly pathological liars too. Any trainer being told that a fatty can maintain a BMI >30 on 1900kcal per day will be snorting in their whey protein shake. You know calories in calories out, yawn.

The placebo group lost 64g of fat per day, which is about 600kcal. This was on 1570kcal/day. So, just by arithmetic, they should previously really have been eating 1570 + 600 = 2170kcal/d to have been weight stable. They claimed to have been eating 1953kcal/d. That's not so far out given the accuracy of food tables. Maybe these were the honest ones.

But the diazoxide group lost 1660kcal/d of fat every day while eating 1570kcal/day of "food" (Slimefast). Does this mean that they had originally been eating 1570 + 1660 = 3230kcal/d to maintain their weight pre study? Now these people claimed 1977kcal/day. Lying porkers. You can't trust anyone. Least of all a fatty. But then everyone lies according to Gibney!

Let's get real. I think both groups ate just 1570kcal/d and skipped the gym. The diazoxide group used all of those calories PLUS 1660kcal/d of their own fatty tissue. The placebo group appeared to use that 1570kcal plus 600kcal of their own fat, but this is an average over time. They lost more than this initially per day, but by the end of the study they didn't look to be loosing any weight at all on those 1570kcal. By week eight they USED 1570kcal/d and that was it. They hadn't lost much weight anyway and now they were weight stable on the same energy consumption that had the diazoxide group loosing consistently. And this was at a much lower energy intake than they had possibly "under reported" at enrollment.

To go back to that apparent idiot Taubes, the problem with fat people is that they do not have access to their fatty tissue. It's only "there" as an energy source when insulin levels are low enough to allow HSL (hormone sensitive lipase) to work. Slimfast drops insulin a bit compared to the SAD, in this study from 204pmol/l to 174pmol/l (neither statistically significant nor biologically significant, after a few weeks anyway). Slimfast plus diazoxide dropped insulin from 168pmol/l to 108pmol/l (statistically p<0.01, biologically weight loss continued).

So where did the energy go to in the diazoxide group, and why did the placebo group stop loosing weight on a marked calorie deficit? Thermodynamics rules. No evaporating calories.

Well, a calorie is a calorie is a calorie. You can't burn what you ain't got. On Slimfast alone (I suspect low fat, low protein, some carbs to keep insulin up almost as much as the SAD) stored adipose tissue is just not available. Lugging around a body with BMI of >30 takes calories. If you don't have the calories, you don't do this. No sneaking to gym for this group, and I bet they were dreaming of donuts by week six, if not before.

In the diazoxide group there were significant periods of time when fatty tissue was available to supply calories because insulin was low. Use it AND loose it, calories that is. Lifting a 150kg body takes calories. If they are available, you can do it, you do do it. You don't need a gym when you weigh this much and have found access to all of that energy in your adipose tissue. Just moving around more makes a difference. I weigh 65kg. Putting on a back pack weighing 85kg would cripple me. I'd burn some calories. Heavy people live with this, shifting about takes energy. A lot. You don't have to change your basal metabolic rate. Just how you move.

So just to summarise this paper. Caloric restriction failed in about 7 weeks. Equal caloric restriction plus lowered insulin levels allowed on going weight loss throughout the study period.

Now, imagine the insulin drop without the diazoxide and without the hunger generated by Slimfast. Eating 1570kcal of steak, curly kale, bacon, scrambled eggs, double cream etc etc. The rest of your calories can come from that enormous supply of fat in your abdomen first, then on your bum. Forget about hunger.

You might even have the energy to go to the gym. After all, with all those adipose calories available, you can afford the energy to work out.

Peter

Weight loss; when it's hard

This post is a set of jottings on weight control when it's difficult. It's essentially unreferenced and was produced in response to the enquiry by Windmill/Windmum (same person) in the comments after this previous post.

Many posts ago I mentioned the thought that it was probably perfectly possible to gain weight on a low carb/high fat diet, provided there were adequate calories involved. Because insulin appears to be very important in controlling the activity of lipoprotein lipase, that enzyme which gets fatty acids out of lipoproteins and in to fat, there has to be some other way of doing this transfer when insulin levels are low.

Chris found the enzyme, it's ASP. You can read more here. ASP is Acylation Stimulating Protein. Let's stick to ASP.

This is completely logical. Those of us who eat combined high fat with LC tend to have rather low levels of insulin in our blood stream. Low levels of insulin mean low levels of activity in the lipoprotein lipase just outside our fat cells. If there was no other way of getting fat out of chylomicrons or VLDL particles and in to adipocytes, we LC eaters would be as chronically hypertriglyceridaemic as a diabetic on a low fat diet. No one would want that.

In to the gap steps ASP, which allows us to store the fat from our current meal as adipose tissue for use in the time before our next meal. On intermittent fasting or once daily eating we HAVE to store an awful lot of fat until we next eat. ASP gets fat in to adipocytes for us, without needing an insulin spike. Good.

What gets the fat out of adipocytes? That's hormone sensitive lipase (HSL from here onwards). Actually, even in HSL knockout mice it is quite possible to get fat out of adipocytes and in the circulation. Which system does this I've no idea and, because none of us is a HSL knockout mouse, I don't much care! If HSL is really working well, it will do the job.

So, say we are eating once daily, we can assume ASP will store any fat we eat in excess of our immediate needs, tucked in to our adipocytes. What reduces our weight is when the release of free fatty acids (FFAs) from our adipocytes via HSL is greater than the input via ASP.

Getting FFAs out easily means optimising the activity of HSL. That means lowering insulin. Low insulin allows HSL to work effectively. An effective HSL supplies FFAs to allow our metabolic activity requirements to be met from adipocytes. A freely available energy supply from adipocytes should reduce the need to obtain energy from food, ie less hunger. Ineffective HSL means you need to eat more, because your fat cells are hanging on to their contents. To paraphrase the whole of Good Calories Bad Calories in one phrase:

Excess weight is the result of a failure of adipocytes to release energy, hunger is needed to supply any shortfall needed for metabolism.

Working on this basis, the requirement for weight loss must be to minimise insulin. This allows metabolism to run on the surplus of adipose tissue energy released over dietary energy consumed. On a high fat diet with low insulin levels ASP will still rapidly store most meal derived fat, HSL will subsequently release it as needed.

Ultimately weight loss boils down to lowering insulin levels. So we end up with a need for minimal carbohydrate. On the Optimal Diet basis that would be the lowest amount for a sedentary person to avoid ketosis, say 0.5g/kg of "ideal" weight. If a person is well adapted to a LC/high fat diet then protein requirements can be as low as 0.8g/kg ideal weight. Protein metabolism requires some insulin response and any excess protein will be mostly converted to glucose, which requires a considerable amount of insulin to be used. Fat intake should be relatively low (by Kwasniewski standards only!) to keep total calories below those needed by our metabolism, otherwise ASP will store more fat than HSL will release. HSL will only ever release enough FFA for the metabolic needs in a healthy person.

On top of that basic plan, the basal metabolic rate must be normal. If a person is hypothyroid they will require far less FFAs for their metabolism and so HSL will adjust to this and minimise fat break down. ASP won't, so a high fat diet will produce weight gain if calories are in excess of metabolic needs. Correct and well monitored thyroid medication is needed for this. As most common thyroid problems seem to be auto immune in origin, avoiding gluten seems like a good idea, if it isn't always a good idea. Which it is. BTW both hypo and hyper thyroidism appear to cause insulin resistance. That seems a bit bizarre to me, but there you go.

There seem to be a few teaks available. Tinkering with insulin sensitivity may be worthwhile. If your muscles need a certain amount of insulin to dispose of a given amount of glucose, then the pancreas will produce that insulin. In addition to helping the muscles take up glucose that insulin will inhibit FFA release from adipocytes. Resistance exercise seems to be the best way to increase insulin sensitivity. Doing this shifts that same given amount of glucose on less insulin. Less insulin means less inhibition of HSL, so easier fat loss.

Improving insulin sensitivity can also be achieved by avoiding medication which interferes with the action of insulin. There has to be a balance here. If dumping your antidepressant makes you suicidal, don't do it! Most blood pressure medications can be gradually reduced as blood pressure tends to normalise on LC eating. Corticosteroids are a real bugbear. Again, if they are life saving you have no choice, keep taking them and accept the weight they make you carry. If you are corticosteroid dependent, never forget that acute withdrawl can be fatal.

If you live as far north as Finland then checking and correcting your vitamin D status would be well worth while.

Anyone reading Chris or Emma's blogs will realise that aspirin, and possibly other related salycilates from plants, cause the pancreas the secrete extra insulin. Avoid. Gluten and wheat germ agglutinin (both from wheat, barley and rye) are (or contain) insulin mimetics, avoid. Casein stimulates insulin secretion, avoid. Pharmaceutical NSAID probably do the same as salycilates, avoid if possible.

Coconut oil is interesting. It has a reputation for assisting weight loss, but if gavaged in to the stomach of a chow fed lab rat it will decrease blood glucose and increase blood insulin levels. You don't want to increase your insulin levels if you want to loose weight. There are other plus and minus sides to coconut oil, but I'd keep life simple and avoid it.

That's quite a list. There are probably loads of other tweaks that I've not thought of...

If you are in the same position as Windmill, that must all be pretty depressing to read. If you want to adjust your weight downwards to where you would like it to be, you are stuck with a pretty extreme version of the Optimal Diet, low but adequate in protein, low in carbs, probably eaten as starches as part of the evening meal, fine tuning your thyroid meds and replacing coconut oil with lard. Lard at a moderate level that is. Do everything practical to maintain your insulin sensitivity.

This seems to work (from an off blog comment from Windmill).

The trouble is that it is HARD. This is not OD as myself or Stan eat it. This is kitchen scales, bathroom scales, portions, calculations, limitations, problems eating out, vegetable avoidance, cheese avoidance, gluten avoidance....... Arghhhhhhh

So there is a trade off. It's one hell of a big trade off. Some of us (most of us probably) have it easy, certainly easier than Windmill. But ultimately there is that balance between fats in to adipocytes and fats out of adipocytes. ASP and HSL. Even worse, there is a trade off between what you know you can do, that you have already done successfully in the past, and the real bind of allowing your diet to rule your life and putting some pretty draconian limits on your eating. Does anybody want to do this? Long term, for ever? That's a very personal decision.

Also the final thought must be: What is the healthiest weight, personal preferences aside?

I don't think we know.

Peter